Novel tetrahydropyridine derivatives as renin inhibitors

ABSTRACT

The invention relates to novel tetrahydropyridine derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.

The invention relates to novel compounds of the general formula I. Theinvention also concerns related aspects including processes for thepreparation of the compounds, pharmaceutical compositions containing oneor more compounds of formula I and especially their use as renininhibitors in cardiovascular events and renal insufficiency.Furthermore, some of these compounds can be regarded as inhibitors ofother aspartyl proteases and might therefore be useful as inhibitors ofplasmepsins to treat malaria and as inhibitors of Candida albicanssecreted aspartyl proteases to treat fungal infections.

In the renin-angiotensin system (RAS) the biologically activeangiotensin II (Ang II) is generated by a two-step mechanism. The highlyspecific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I),which is then further processed to Ang II by the less specificangiotensin-converting enzyme (ACE). Ang II is known to work on at leasttwo receptor subtypes called AT₁ and AT₂. Whereas AT₁ seems to transmitmost of the known functions of Ang II, the role of AT₂ is still unknown.

Modulation of the RAS represents a major advance in the treatment ofcardiovascular diseases. ACE inhibitors and AT₁ blockers have beenaccepted to treat hypertension (Waeber B. et al., “The renin-angiotensinsystem: role in experimental and human hypertension”, in Berkenhager W.H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier SciencePublishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5,247S). In addition, ACE inhibitors are used for renal protection(Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J.A. et al., Kidney International, 1994, 45, S156), in the prevention ofcongestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994,28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83)and myocardial infarction (Pfeffer M. A. et al., N. Engl. J. Med., 1992,327, 669).

The rationale to develop renin inhibitors is the specificity of renin(Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrateknown for renin is angiotensinogen, which can only be processed (underphysiological conditions) by renin. In contrast, ACE can also cleavebradykinin besides Ang I and can be by-passed by chymase, a serineprotease (Husain A., J. Hypertens., 1993, 11, 1155). In patientsinhibition of ACE thus leads to bradykinin accumulation causing cough(5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%)(Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234).Chymase is not inhibited by ACE inhibitors. Therefore, the formation ofAng II is still possible in patients treated with ACE inhibitors.Blockade of the AT₁ receptor (e.g. by losartan) on the other handoverexposes other AT-receptor subtypes to Ang II, whose concentration isdramatically increased by the blockade of AT₁ receptors. This may raiseserious questions regarding the safety and efficacy profile of AT₁receptor antagonists. In summary, renin inhibitors are not only expectedto be different from ACE inhibitors and AT₁ blockers with regard tosafety, but more importantly also with regard to their efficacy to blockthe RAS.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994,12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has beencreated with renin inhibitors because of their insufficient oralactivity due to their peptidomimetic character (Kleinert H. D.,Cardiovasc. Drugs, 1995, 9, 645). The clinical development of severalcompounds has been stopped because of this problem together with thehigh cost of goods. Only one compound containing four chiral centers hasentered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493;Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, metabolicallystable, orally bioavailable and sufficiently soluble renin inhibitorsthat can be prepared on a large scale are missing and sought. Recently,the first non-peptide renin inhibitors were described which show high invitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; PatentApplication WO97/093 11; Märki H. P. et al., II Farmaco, 2001, 56, 21).However, the development status of these compounds is not known.

The present invention relates to the unexpected identification of renininhibitors of a non-peptidic nature and of low molecular weight. Orallyactive renin inhibitors of long duration of action which are active inindications beyond blood pressure regulation where the tissularrenin-chymase system may be activated leading to pathophysiologicallyaltered local functions such as renal, cardiac and vascular remodeling,atherosclerosis, and possibly restenosis, are described.

In particular, the present invention relates to novel compounds of thegeneral formula I.

wherein

-   -   X and W represent independently a nitrogen atom or a CH-group;    -   V represents —(CH₂)_(r)—; -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t)—;        —(CH₂)_(s)-A-; —(CH₂)₂-A-(CH₂)_(u)—; -A-(CH₂)_(v)—B—;        —CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—B—;        —CH₂—CH₂—CH₂-A-CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂-A-CH₂—;        -A-CH₂—CH₂—B—CH₂—CH₂—; —CH₂-A-CH₂—CH₂—B—CH₂—;        —CH₂-A-CH₂—CH₂—CH₂—B—; —CH₂—CH₂-A-CH₂—CH₂—B—;    -   A and B independently represent —O—; —S—; —SO—; —SO₂—;    -   U represents aryl; heteroaryl;    -   T represents —CONR¹—; —(CH₂)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;        —(CH₂)_(p)N(R¹)SO₂—; —COO—; —(CH₂)_(p)OCONR¹—;        —(CH₂)_(p)N(R¹′)CONR¹—;    -   Q represents lower alkylene; lower alkenylene;    -   M represents hydrogen; cycloalkyl; aryl; heterocyclyl;        heteroaryl;    -   R¹ and R¹′ independently represent hydrogen; lower alkyl; lower        alkenyl; lower alkinyl; cycloalkyl; aryl; cycloalkyl-lower        alkyl;    -   p is the integer 1, 2, 3 or 4;    -   r is the integer 3, 4, 5 or 6;    -   s is the integer 2, 3, 4 or 5;    -   t is the integer 1, 2, 3 or 4;    -   u is the integer 1, 2 or 3;    -   v the integer to 2, 3 or 4;    -   and optically pure enantiomers, mixtures of enantiomers such as        racemates, diastereomers, mixtures of diastereomers,        diastereomeric racemates, mixtures of diastereomeric racemates,        and the meso-form; as well as pharmaceutically acceptable salts,        solvent complexes and morphological forms.

In the definitions of general formula I—if not otherwise stated—the termlower alkyl, alone or in combination with other groups, means saturated,straight and branched chain groups with one to seven carbon atoms,preferably one to four carbon atoms that can be optionally substitutedby halogens. Examples of lower alkyl groups are methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andheptyl. The methyl, ethyl and isopropyl groups are preferred.

The term lower alkoxy refers to a R—O group, wherein R is a lower alkyl.Examples of lower alkoxy groups are methoxy, ethoxy, propoxy,iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term lower alkenyl, alone or in combination with other groups, meansstraight and branched chain groups comprising an olefinic bond and twoto seven carbon atoms, preferably two to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkenyl are vinyl,propenyl or butenyl.

The term lower alkinyl, alone or in combination with other groups, meansstraight and branched chain groups comprising a triple bond and two toseven carbon atoms, preferably two to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkinyl areethinyl, propinyl or butinyl.

The term lower alkylene, alone or in combination with other groups,means straight and branched divalent chain groups with one to sevencarbon atoms, preferably one to four carbon atoms, that can beoptionally substituted by halogens. Examples of lower alkylene areethylene, propylene or butylene.

The term lower alkenylene, alone or in combination with other groups,means straight and branched divalent chain groups comprising an olefinicbond and two to seven carbon atoms, preferably two to four carbon atoms,that can be optionally substituted by halogens. Examples of loweralkenylene are vinylene, propenylene and butenylene.

The term lower alkylenedioxy, refers to a lower alkylene substituted ateach end by an oxygen atom. Examples of lower alkylenedioxy groups arepreferably methylenedioxy and ethylenedioxy.

The term lower alkylenoxy refers to a lower alkylene substituted at oneend by an oxygen atom. Examples of lower alkylenoxy groups arepreferably ethylenoxy and propylenoxy.

The term halogen means fluorine, chlorine, bromine or iodine, preferablyfluorine, chlorine and bromine.

The term cycloalkyl alone or in combination, means a saturated cyclichydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which can beoptionally mono-, di-, or trisubstituted independently by lower alkyl,lower alkenyl, lower alkenylene, lower alkoxy, lower alkylenoxy, loweralkylenedioxy, hydroxy, halogen, —CF₃, —NR¹R¹′, —NR¹C(O)R¹′,—NR¹S(O)₂R¹′, —C(O)NR¹R¹′, lower alkylcarbonyl, —COOR¹, —SR¹, —SOR¹,—SO₂R¹, —SO₂NR¹R¹¹. The cyclopropyl group is a preferred group.

The term aryl, alone or in combination, relates to the phenyl, thenaphthyl or the indanyl group, preferably the phenyl group, which can beoptionally mono-, di-, tri-, tetra- or pentasubstituted independently bylower alkyl, lower alkenyl, lower alkinyl, lower alkenylene or loweralkylene forming with the aryl ring a five- or six-membered ring, loweralkoxy, lower alkylenedioxy, lower alkylenoxy, hydroxy, hydroxy-loweralkyl, halogen, cyano, —CF₃, —OCF₃, —NR¹R¹′, —NR¹R¹′-lower alkyl,—NR¹C(O)R¹′, —NR₁S(O)₂R¹′, —C(O)NR¹R¹′, —NO₂, lower alkylcarbonyl,—COOR¹, —SR¹, —S(O)R¹, —S(O)₂R¹, —SO₂NR¹R¹′, benzyloxy. Preferredsubstituents are halogen, lower alkoxy, lower alkyl.

The term aryloxy refers to an Ar—O group, wherein Ar is an aryl. Anexample of aryloxy groups is phenoxy.

The term heterocyclyl, alone or in combination, means saturated orunsaturated (but not aromatic) five-, six- or seven-membered ringscontaining one or two nitrogen, oxygen or sulfur atoms which may be thesame or different and which rings can be optionally substituted withlower alkyl, hydroxy, lower alkoxy and halogen. The nitrogen atoms, ifpresent, can be substituted by a COOR² group. Examples of such rings arepiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl,tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl,dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.

The term heteroaryl, alone or in combination, means six-memberedaromatic rings containing one to four nitrogen atoms; benzofusedsix-membered aromatic rings containing one to three nitrogen atoms;five-membered aromatic rings containing one oxygen, one nitrogen or onesulfur atom; benzofused five-membered aromatic rings containing oneoxygen, one nitrogen or one sulfur atom; five-membered aromatic ringscontaining one oxygen and one nitrogen atom and benzofused derivativesthereof; five-membered aromatic rings containing a sulfur and a nitrogenor an oxygen atom and benzofused derivatives thereof; five-memberedaromatic rings containing two nitrogen atoms and benzofused derivativesthereof; five-membered aromatic rings containing three nitrogen atomsand benzofused derivatives thereof, or a tetrazolyl ring. Examples ofsuch ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl,pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl,thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl,isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl, quinoxalinyl.Such rings may be adequatly substituted with lower alkyl, lower alkenyl,lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy,lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen,cyano, —CF₃, —OCF₃, —NR¹R¹′, NR¹R¹′-lower alkyl, —N(R¹)COR¹,—N(R¹)SO₂R¹, —CONR¹R¹′, —NO₂, lower alkylcarbonyl, —COOR¹, —SR¹,—S(O)R¹, —S(O)₂R¹, —SO₂NR¹R¹′, another aryl, another heteroaryl oranother heterocyclyl and the like.

The term heteroaryloxy refers to a Het-O group, wherein Het is aheteroaryl.

It is understoood that the substituents outlined relative to theexpressions cycloalkyl, heterocyclyl, heteroaryl and aryl have beenomitted in the definitions of the general formula I and in claims 1 to 6for clarity reasons but the definitions in formula I and in claims 1 to6 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrochloric orhydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formicacid, acetic acid, maleic acid, tartaric acid, benzoic acid,methanesulfonic acid, p-toluenesulfonic acid, and the like that are nontoxic to living organisms or in case the compound of formula I is acidicin nature with an inorganic base like an alkali or earth alkali base,e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and thelike.

The compounds of the general formula I can contain one or moreasymmetric carbon atoms and may be prepared in form of optically pureenantiomers, mixtures of enantiomers such as racemates, diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, and the meso-form and pharmaceuticallyacceptable salts therof.

The present invention encompasses all these forms. Mixtures may beseparated in a manner known per se, i.e. by column chromatography, thinlayer chromatography, HPLC or crystallization.

A group of preferred compounds of general formula I are those wherein X,W, V, and U, are as defined in general formula I and wherein

-   -   T is —CONR¹—;    -   Q is a methylene;    -   M is hydrogen; aryl; heteroaryl.

Another group of more preferred compounds of general formula I are thosewherein X, W, T, Q, and M are as defined in general formula I andwherein

-   -   V is one of the following groups:    -   —CH₂CH₂O—; —CH₂CH₂CH₂O—; —OCH₂CH₂O—    -   and U is as defined in general formula I above.

Another group of even more preferred compounds of general formula I arethose wherein V, U, T, Q, and M are as defined in general formula I andwherein

-   -   X and W represent CH.

Another group of more preferred compounds of general formula I are thosewherein X, W, V, Q, T, and M are as defined in general formula I andwherein

-   -   U is a mono-, di-, or trisubstituted phenyl. Preferred        substituents are independently halogen or lower alkyl, lower        alkoxy, trifluoromethyl, trifluoromethoxy.

Especially preferred compounds of general formula I are those selectedfrom the group consisting of:

-   -   4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid [2-(2-chlorophenyl)ethyl]methylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl-1,2,5,6-tetrahydropyridi-ne-3-carboxylic        acid [2-(2-chlorophenyl)ethyl]methylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylic        acid 2-phenethylmethylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylic        acid (2-chlorobenzyl)methylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid [2-(2-chlorophenyl)ethyl]methylamide,    -   4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid 2-phenethylmethylamide,    -   4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)methylamide,    -   4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid [2-(2-chlorophenyl)ethyl]methylamide,    -   4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid 2-phenethylmethylamide,    -   4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)methylamide,    -   4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-fluorobenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3-trifluoromethylbenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-methylbenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-[2-(3-methoxyphenoxy)ethyl]amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-m-tolyloxyethyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid [2-(2-chlorophenyl)ethyl]cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-[2-(4-fluorophenyl)ethyl]amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        and acid cyclopropyl-(2-o-tolylethyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-p-tolylethyl)amide,    -   4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3-trifluoromethylbenzyl)amide,    -   4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-methylbenzyl)amide,    -   4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropylphenethylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-methylbenzyl)amide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropylphenethylamide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-o-tolylethyl)amide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-p-tolylethyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3,4-dimethoxybenzyl)amide,    -   4-f{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-6-fluorobenzyl)cyclopropylamide,    -   4-14-[3-(2,3,6-trifluorophenoxy)propyl]phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propylphenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3-fluoro-2-methylbenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3-methylbenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-difluorobenzyl)amide,    -   4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (3-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl})1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxyphenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxyphenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methylbenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (3-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy)phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-trifluoromethoxybenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-difluorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,4-dimethoxybenzyl)amide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt,    -   4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)-cyclopropylamide,    -   4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,3-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(4-chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dichlorobenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-trifluoromethoxybenzyl)amide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(5-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (3-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl)}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-difluorobenzyl)amide,    -   4-{4-[2-(2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide,    -   4-{4-[2-(2,3-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[2-(2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxy-benzyl)amide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide,    -   4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)ethylamide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid cyclopropyl-(3,5-dimethoxybenzyl)amide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-(4-[2-(4-chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(2,3-dimethylbenzyl)amide,    -   4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide,    -   4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-bromobenzyl)cyclopropylamide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid cyclopropyl-(3-methoxybenzyl)amide,    -   4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide,    -   4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-3,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2-chloro-6-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,3-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide,    -   4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide, and    -   4-{4-[2-(2,6-dichlorophenoxy)ethoxy]phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylic        acid (2-chlorobenzyl)cyclopropylamide.

The compounds of general formula I and their pharmaceutically acceptablesalts may be used as therapeutics e.g. in form of pharmaceuticalcompositions. They may especially be used in the treatment and/orprophylaxis of cardiovascular and renal diseases. Examples of suchdiseases are hypertension, coronary diseases, cardiac insufficiency,renal insufficiency, renal and myocardial ischemia, and renal failure.They can also be used to prevent restenosis after balloon or stentangioplasty, to treat erectile dysfunction, glomerulonephritis, renalcolic, and glaucoma. Furthermore, they can be used in the therapy andthe prophylaxis of diabetic complications, complications of vascular orcardiac surgery or after organ transplantation, complications ofcyclosporin treatment, as well as other diseases presently known to berelated to the RAS.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are related to the RASsuch as hypertension, coronary diseases, cardiac insufficiency, renalinsufficiency, renal and myocardial ischemia, and renal failure, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The invention farther relates to the use of compounds of general formulaI as defined above for the treatment and/or prophylaxis of diseaseswhich are associated with the RAS such as hypertension, coronarydiseases, cardiac insufficiency, renal insufficiency, renal andmyocardial ischemia, and renal failure.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with the RAS such ashypertension, coronary diseases, cardiac insufficiency, renalinsufficiency, renal and myocardial ischemia, and renal failure. Thesemedicaments may be prepared in a manner known per se.

The compounds of formula I may also be used in combination with one ormore other therapeutically useful substances e. g. with other renininhibitors, with ACE-inhibitors, with angiotensin-receptor antagonists,with diuretics, with calcium channel blockers, with endothelin receptorsantagonists or with other drugs beneficial for the prevention or thetreatment of cardiovascular events or renal insufficiency.

All forms of prodrugs leading to an active component comprised ingeneral formula I are included in the present invention.

The compounds of general formula I can be manufactured by the methodsgiven below, by the methods given in the examples or by analogousmethods.

Preparation of the Precursors:

Precursors are compounds that were prepared as key intermediates and/orbuilding blocks and which were suitable for further transformations inparallel chemistry.

Ideal starting materials are any commercially available4-oxo-piperidine-3-carboxylic acid ester derivatives, for instance1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester, possibly as asalt. For practical purposes, a transesterification (for instanceaccording to Seebach D., et al., Synthesis, 1982, 138) to another esterderivative A (wherein R^(a) is optionally a lower alkyl, a loweralkenyl, or a benzyl group), thereafter a change in the N-protectinggroup (PG: all abreviations are outlined at the beginning of the chapterExamples) to a derivative of type B, may be necessary (Scheme 1).

Formation of the vinyl triflate C, followed by a coupling catalysed by aPd(0) complex may lead to tetrahydropyridine derivatives of type D,wherein R^(b) optionally represents any U-V group as defined in generalformula I or a chemical precursor of such a group (Scheme 2).

If, for instance, R^(b) is a linker ending with a silanyl ether,compounds of type D are deprotected to compounds of type E, then coupledto a phenol or aromatic alcohol using a Mitsunobu reaction, leading toderivatives of type F wherein V and U have the meaning given in generalformula I above (Scheme 3). The ester F is optionally then be cleaved byany suitable method to lead to precursor G.

Also, a compound of type D may be reduced with DIBAL to a compound oftype M that can be then oxidized to a compound of type N with e.g. theDess-Martin periodinane (Scheme 4). Aldehyde N may then be transformedto a compound of type O by reductive amination, which can be acylated toa derivative of type Q′ wherein Q and M have the meaning given ingeneral formula I above. On the other hand, compounds of type M can bethen acylated following standard procedures to esters or carbamates oftype P.

Also, as shown in Scheme 5, a precursor of type T can be prepared inthree steps from a compound of type D, by saponification (compound oftype R), amide lo coupling (compound of type S) and finallydesilylation.

Preparation of Bromoaryl Derivatives

For the coupling of compounds of type C to tetrahydropyridinederivatives of type D, it can be necessary to prepare the bromoarylcomponents needed as described in Scheme 6. A Mitsunobu coupling(→compounds of type H) or the alkylation of an alcohol with a benzylicchloride (or bromide,→compounds of type J) are often the most convenientmethods. Derivative K was prepared in one step from1-(3-chloropropoxymethyl)-2-methoxybenzene by reaction with4-bromophenol (Vieira E. et al., Bioorg. Med. Chem. Letters, 1999, 9,1397). Other methods for the preparation of ethers or thioethers, like aWilliamson synthesis, might be used as well (see e.g. March, J,“Advanced Organic Chemistry”, 5^(th) ed., John Wiley and sons, 2001).

Preparation of the Secondary Amines

It may be necessary to prepare secondary amines as well. This can bedone by reductive amination from the corresponding amine and aldehyde,or by amide coupling, from the corresponding amine and carboxylic acid,followed by reduction with LAH or borane. These standard procedures arewell-described in the literature.

Preparation of Final Compounds

A compound of type G can be coupled to the amine to yield amides of typeL wherein V, U and M have the meaning given in general formula I above.Removal of the N-protecting group (PG) leads to a final compound,wherein V, U, Q and M have the meaning given in general formula I above(Scheme 7).

Also, compounds of type P or Q′ (Scheme 4) may be processed further asindicated in Scheme 3, then deprotected as indicated in Scheme 7, tolead to final compounds as defined in general formula I.

From a precursor of type T a final compound can be prepared by aMitsunobu-type reaction, followed by deprotection (Scheme 8).

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, e. g. in the form ofpharmaceutical preparations for enteral, parenteral, or topicaladministration. They can be administered, for example, perorally, e. g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e. g. in theform of suppositories, parenterally, e. g. in the form of injectionsolutions or infusion solutions, or topically, e. g. in the form ofointments, creams or oils.

The production of pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable acid addition salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants in a manner known per se.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injections are, for example, water, alcohols,polyols, glycerols and vegetable oils. Suitable carrier materials forsuppositories are, for example, natural or hardened oils, waxes, fatsand semi-liquid or liquid polyols. Suitable carrier materials fortopical preparations are glycerides, semi-synthetic and syntheticglycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquidfatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 50 mg to about 500 mg, comes into consideration. Forchildren the dosage has to be adapted to the body weight and age.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 5-200 mg of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

General Remarks

The following compounds were prepared according to the proceduresdescribed for the synthesis of compounds encompassed by the generalformula I. All compounds were characterized by ¹H-NMR (300 MHz) andoccasionally by ¹³C-NMR (75 MHz) (Varian Oxford, 300 MHz), by LC-MS: A:2 min <t_(R)<10 min; (Waters Micromass; ZMD-platform with ESI-probe withAlliance 2790 HT; Column: 2×30 mm, Gromsil ODS4, 3 μM, 120A; Gradient:0-100% acetonitril in water, 6 min, with 0.05% formic acid, flow: 0.45mL/min; t_(R) given in min.), B: 0.1 min <t_(R)<2 min; (Finnigan AQAwith ESI-probe with HP 110 DAD and HP110 binary pump; column: DevelosilRP-AQUEOUS, 5 μM, 4.6 mm×50 mm; gradient: 5-95% methanol in water (0.04%TFA), 1 min, 95% methanol in water (0.04% TFA) 0.4 min, 4.5 mL/min.), byTLC (TLC-plates from Merck, Silica gel 60 F₂₅₄). LC-MS- and TLC-dataonly are given hereby.

Abbreviations

-   ACE Angiotensin Converting Enzyme-   Ang Angiotensin-   aq. aqueous-   Bn Benzyl-   Boc tert-Butyloxycarbonyl-   BSA Bovine serum albumine-   BuLi n-Butyllithium-   conc. Concentrated-   DIBAL Diisobutylaluminium hydride-   DIPEA Diisopropylethylanline-   DMAP 4-N,N-Dimethylaminopyridine-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EDC.HCl Ethyl-N,N-dimethylaminopropylcarbodiimide hydrochloride-   EIA Enzyme immunoassay-   eq. equivalent-   Et Ethyl-   EtOAc Ethyl acetate-   FC Flash Chromatography-   HOBt Hydroxybenzotriazol-   LAH Lithium aluminium hydride-   MeOH Methanol-   org. organic-   PBS Phosphate Buffer Saline-   PG protecting group-   Ph Phenyl-   RAS Renin Angiotensin System-   RP18 Reversed phase column, filled with C₁₈ hydrocarbon-   rt room temperature-   sol. Solution-   TBDMS tert-Butyldimethylsilyl-   Tf Trifluoromethylsulfonyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin Layer Chromatography-   TMAD N,N,N′,N′-Tetramethylazodicarboxamide    General Procedures    General Procedure A for Amide Coupling

A sol. of the desired carboxylic acid (1.00 eq), the desired amine (2.00eq), EDC.HCl (1.10 eq.), HOBt (cat. amount), DMAP (cat. amount) andDIPEA (2.00 eq.) in CH₂Cl₂ (20 mL/g of acid) was stirred at rtovernight. The reaction mixture was either washed over diatomic earth(Isolute Sorbent Technology, Johnson, C. R., et al., Tetrahedron, 1998,54, 4097), or washed with aq. 1M HCl, and the org. extracts wereevaporated under reduced pressure. The residue was used without furtherpurification.

General Procedure B for the Removal of a Boc-Protecting Group

The starting material was dissolved in CH₂Cl₂ (10 mL/g of startingmaterial) and the sol. was cooled to 0° C. 4M HCl in dioxane (samevolume as CH₂Cl₂) was added and the reaction mixture was left for 90 minat rt. The solvents were removed under reduced pressure. Purification ofthe residue by HPLC led to the desired compound.

Typical Procedure C for Amide Formation from Acid Chlorides

To a sol. of the acid chloride (1 eq.) in CH₂Cl₂ (2.5 mL/mmol) at 0° C.the amine (3 eq.) was added. The mixture was stirred for 3 h whilewarming up slowly to rt. If necessary, more CH₂Cl₂ was added, then thereaction mixture was washed with aq. sat. NaHCO₃ (1×) and aq. 1M HCl(1×). The extracts were dried over MgSO₄ and the solvents were removedunder reduced pressure. The obtained product was used without furtherpurification.

Typical Procedure D for the Reduction of an Amide to an Amine with LAH

To a sol. of the amide (1 eq.) was dissolved in THF (3 mL/mmol) LAH (1Min THF, 3 eq.) was added carefully. The mixture was stirred at rt for 30min, then heated to 60° C. for 3 h before it was allowed to cool down tort, then to 0° C. For ×g of LAH initially added, was added ×g of water,then ×g of aq. 15% NaOH, and finally 3×g of water again. The resultingmixture was stirred overnight, filtered, and the precipitate washed withEtOAc. The filtrate was evaporated under reduced pressure and theresidue diluted in a small amount of MeOH. The sol. was passed through apad of SCX silica gel (sulfonic acid). Elution started with MeOH,followed by NH₃/MeOH. The amines eluted with the second second eluent.The solvents were removed under reduced pressure. The isolated amineswere either used without further purification or purified by HPLC,depending on the purity.

Typical Procedure E for Reductive Amination

To a solution of aldehyde (1 eq.) in MeOH (0.5 mL/mmol) was added anamine (1.2 eq.). The solution was stirred for 2 h. Sodium borohydride(1.2 eq.) was added portionwise at 0° C. and then stirring wascontinued, at rt, for 4 h. A solution of NaOH IN was added and the MeOHwas evaporated. The mixture was extracted with EtOAc twice and theorganic layer was washed with brine, dried over Na₂SO₄ and filtered. Thesolvent was removed under reduced pressure. The isolated amines wereeither used without further purification or purified by flashchromatography (EtOAc/heptane: 2/8), depending on the purity.

Preparation of the Secondary Amines

(2-Chlorobenzyl)cyclopropylamine

Synthesized according to typical procedures C and D from 2-chlorobenzoylchloride and cyclopropylamine.

(2-Chlorobenzyl)ethylamine

See Ishihara, Y; et al.; Chem. Pharm. Bull., 1991, 39, 3225.

Cyclopropyl-(3,5-dimethoxybenzyl)amine

Synthesized according to typical procedure E from2,5-dimethoxybenzaldehyde and cyclopropylamine.

Cyclopropyl-(2-fluoro-5-methoxybenzyl)amine

Synthesized according to typical procedure E from2-fluoro-5-methoxybenzaldehyde and cyclopropylamine.

Cyclopropyl-(3-methoxybenzyl)amine

Synthesized according to typical procedure E from 3-methoxybenzaldehydeand cyclopropylamine.

Cyclopropyl-(3,4-dimethoxybenzyl)amine

Synthesized according to typical procedure E from3,4-dimethoxybenzaldehyde and cyclopropylamine.

(2-Chloro-3-trifluoromethylbenzyl)cyclopropylamine

Synthesized according to typical procedure E from2-chloro-3-trifluoromethylbenzaldehyde and cyclopropylamine.

(6-Chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamine

Synthesized according to typical procedure E from6-chlorobenzo[1,3]dioxole-5-carbaldehyde and cyclopropylamine.

(2-Bromobenzyl)cyclopropylamine

Synthesized according to typical procedure E from 2-bromobenzaldehydeand cyclopropylamine.

Cyclopropyl-(2,3-dimethylbenzyl)amine

Synthesized according to typical procedure E from2,3-dimethylbenzaldehyde and cyclopropylamine.

Cyclopropyl-(3,5-difluorobenzyl)amine

Synthesized according to typical procedure E from3,5-difluorobenzaldehyde and cyclopropylamine.

(2,3-Dichlorobenzyl)cyclopropylamine

Synthesized according to typical procedure E from2,3-dichlorobenzaldehyde and cyclopropylamine.

Cyclopropyl-(3-trifluoromethoxybenzyl)amine

Synthesized according to typical procedure E from3-trifluoromethoxy-benzaldehyde and cyclopropylamine.

Cyclopropyl-(3-methylbenzyl)amine

Synthesized according to typical procedure E from 3-methylbenzaldehydeand cyclopropylamine.

(3-Chlorobenzyl)cyclopropylamine

Synthesized according to typical procedure E from 3-chlorobenzaldehydeand cyclopropylamine.

Cyclopropyl(2-fluorobenzyl)amine

Synthesized according to typical procedure E from 2-fluorobenzaldehydeand cyclopropylamine.

Cyclopropyl-(2-methylbenzyl)amine

Synthesized according to typical procedure E from 2-methylbenzaldehydeand cyclopropylamine.

Cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amine

Synthesized according to typical procedures C and D from(4-methoxyphenoxy)-acetic acid and cyclopropylamine.

Cyclopropyl-[2-(3-methoxyphenoxy)ethyl]amine

Synthesized according to typical procedures C and D from(3-methoxyphenoxy)-acetic acid and cyclopropylamine.

Cyclopropyl-(2-m-tolyloxyethyl)amine

Synthesized according to typical procedures C and D from m-tolylaceticacid and cyclopropylamine.

[2-(2-Chlorophenyl)ethyl]cyclopropylamine

Synthesized according to typical procedures C and D from(2-chlorophenyl)-acetic acid and cyclopropylamine.

Cyclopropyl-[2-(4-fluorophenyl)ethyl]amine

Synthesized according to typical procedures C and D from(4-fluorophenyl)acetic acid and cyclopropylamine.

Cyclopropyl-(2-o-tolylethyl)amine

Synthesized according to typical procedures C and D from o-tolylaceticacid and cyclopropylamine.

Cyclopropyl-(2-p-tolylethyl)amine

Synthesized according to typical procedures C and D from p-tolylaceticacid and cyclopropylamine.

Preparation of the Precursors

4-Oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(B)

A suspension of 1-benzyl-4-oxopiperidine-3-carboxylic acid methyl esterhydrochloride (5.00 g, 17.6 mmol), triethylamine (2.45 mL, 17.6 mmol)and Boc₂O (4.20 g, 20.0 mmol) in EtOH (30 mL) was purged with N₂. Pd/C(10%, 600 mg) was added and the suspension purged with H₂. The reactionmixture was stirred under an H₂-atmosphere for 24 h and then filteredthrough Celite. The filtrate was evaporated under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4→2:3) yielded thetitle compound (4.02 g, 89%). R_(f)=0.60 (EtOAc/heptane 1:1). LC-MS:R_(t)=1.09 min, ES+=202.03.

Compounds of Type C

1-Benzyl-4-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydropyridine-3-carboxylicacid ethyl ester (C1)

To a suspension of 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethylester hydrochloride (1.50 g, 5.04 mmol) in THF (30 mL) NaH (about 60% inoil, 600 mg, about 15 mmol) was added at 0° C. As the suspension turnedthick CH₂Cl₂ (20 mL) was added. The ice bath was removed and Tf₂NPh(2.68 g, 7.50 mmol) was added. The mixture was stirred overnight and icewas added. The mixture was washed with aq. 10% Na₂CO₃ (1×) and the org.extracts were dried over MgSO₄ and filtered. The solvents were removedunder reduced pressure and purification of the residue by FC(EtOA/heptane 1:9→1:4→2:3) yielded the title compound (2.10 g, almostquantitative yield). R_(f)=0.50 (EtOAc/heptane 1:1). LC-MS: R_(t)=4.65min, ES+: 394.12.

4-Trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (C2)

To a sol. of compound B (4.00 g, 15.6 mmol) in THF (100 mL) at 0° C. wasadded NaH (suspension in oil, 55-65%, 1.20 g, about 31 mmol). Thesuspension was stirred for 30 min at 0° C. and Tf₂NPh (8.27 g, 23.1mmol) was added. The ice bath was removed and the reaction mixturestirred for 3 days at rt. Ice was added and the solvents were removedunder reduced pressure. The residue was diluted with EtOAc and washedwith aq. 10% Na₂CO₃. The org. extracts were dried over MgSO₄, filteredand the solvent removed under reduced pressure. Purification of theresidue by SC (EtOAc/heptane 1:4) yielded the title compound (5.19 g,86%). LC-MS: R_(t)=1.17, ES+=374.96.

Compounds of Type D

1-Benzyl-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid ethyl ester (D1)

To a sol. of 4-bromo-1-[3-(2-methoxybenzyloxy)propoxy]benzene (2.81 g,8.01 mmol) in THF (50 mL) at −78° C. n-BuLi (1.5M in hexane, 5.60 mL,8.41 mmol) was added. After 30 min ZnCl₂ (1M in THF, 9.00 mL, 9.00 mmol)was added and the mixture was allowed to warm up to rt. Vinyl triflateC1 (2.10 g, 5.34 mmol) and Pd(PPh₃)₄ (154 mg, 0.134 mmol) were added andthe mixture stirred at rt for 4.5 h. Ice was added, the mixture wasdiluted with EtOAc and washed with aq. 1M NaOH (1×). The org. extractswere dried over MgSO₄, filtered, and the solvents were removed underreduced pressure. Purification of the residue by FC (EtOAc/heptane1:9→1:4→2:3→3:2) led to the title compound (2.25 g, 82%). R_(f)=0.32(EtOAc/heptane 1:1). LC-MS: R_(t)=4.05 min, ES+=516.23.

4-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (D2)

To a sol. of [3-(4-bromophenyl)propoxy]-tert-butyldimethylsilane(Kiesewetter D. O., Tetrahedron Asymmetry, 1993, 4, 2183; 6.19 g, 19.7mmol) in THF (100 mL) at −78° C. was added n-BuLi (1.5M in hexane, 14.0mL, 21.0 mmol). The sol. was stirred at −78° C. for 30 min and ZnCl₂ (1Min THF, 22.3 mL, 22.3 mmol) was added. The resulting sol. was allowed towarm to rt and compound C2 (5.10 g, 13.1 mmol) and Pd(PPh₃)₄ (300 mg,0.26 mmol) were added. After 20 min at rt ice was added to the reactionmixture. The solvents were removed under reduced pressure and theresidue diluted with EtOAc. This mixture was washed with aq. 1M NaOH.The org. extracts were dried over MgSO₄, filtered and the solventsremoved under reduced pressure. Purification of the residue by FC(EtOAc/heptane 1:9) led to the title compound (5.77 g, 90%). LC-MS:R_(t)=7.27 min, ES+=512.54.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (D3)

As described for compound D2 but from[2-(4-bromo-phenoxy)ethoxy]-tert-butyldimethylsilane (Morita, C.; etal.al.; Heterocycles, 2000, 52, 1163; 49.5 g, 149 mmol), BuLi (1.6M inhexane, 94 mL, 150 mmol), ZnCl₂ (1M in THF, 200 mL, 200 mmol), compoundC2 (37.0 g, 95 mmol), Pd(PPh₃)₄ (2.75 g, 2.38 mmol) and THF (750 mL).Purification by FC yielded the title compound (36.6 g, 78%). LC-MS:R_(t)=1.20 min, ES+=492.34.

Compounds of Type E

4-[4-(3-Hydroxypropyl)phenyl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (E1)

TBAF (1.90 g, 6.00 mmol) was added to a sol. of compound D2 (1.95 g,4.00 mmol) in THF (40 mL). The reaction mixture was stirred for 6 h atrt and diluted with EtOAc. The resulting mixture was washed with waterand brine. The org. extracts were dried over MgSO₄, filtered and thesolvents removed under reduced pressure. Purification of the residue byFC (EtOAc/heptane 2:3) yielded the title compound (1.27 g, 84%). LC-MS:R_(t)=1.06, ES+=376.18.

4-[4-(2-Hydroxyethoxy)phenyl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester-3-methyl ester (E2)

As described for compound E1 but from compound D3 (5.63 g, 11.4 mmol),TBAF (5.41 g, 17.1 mmol) and THF (115 mL). Purification by FC yieldedthe title compound (3.46 g, 80%). LC-MS: R_(t)=1.01; ES+=378.22.

Compounds of Type F

4-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-5,6dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F1)

A sol. of compound E1 (750 mg, 2.00 mmol), 2-bromo-5-fluorophenol (0.334mL, 3.00 mmol), azodicarboxyl dipiperidide (757 mg, 3.00 mmol),tri-n-butylphosphine (0.987 mL, 4.00 mmol) and DIPEA ( 0.035 mL, 0.20mmoL) in toluene (20 mL) was stirred for 1 h at rt, then for 2 h at 60°C. The reaction mixture was allowed to cool to rt, was diluted withEtOAc and washed with water. The org. extracts were dried over MgSO₄,filtered and the solvents were removed under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4→3:7) led to thetitle compound (898 mg, 82%). LC-MS: R_(t)=6.43 min, ES+=570.00.

4-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F2)

A sol. of compound E1 (375 mg, 1.00 mmol), 2-chlorophenol (0.153 mL,1.50 mmol), azodicarboxyl dipiperidide (378 mg, 1.50 mmol),tri-n-butylphosphine (0.493 mL, 2.00 mmol) and DIPEA ( 0.018 mL, 0.10mmoL) in toluene (10 mL) was stirred for 1 h at rt, then for 2 h at 60°C. The reaction mixture was allowed to cool to rt, was diluted withEtOAc and washed with water. The org. extracts were dried over MgSO₄,filtered and the solvents were removed under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4→3:7) led to thetitle compound (374 mg, 77%). LC-MS: R_(t)=1.39 min, ES+=486.13.

4-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F3)

A sol. of compound E1 (375 mg, 1.00 mmol), 2,5-difluorophenol (195 mg,1.50 mmol), azodicarboxyl dipiperidide (378 mg, 1.50 mmol),tri-n-butylphosphine (0.493 mL, 2.00 mmol) and DIPEA ( 0.018 mL, 0.10mmoL) in toluene (10 mL) was stirred for 1 h at rt, then for 2 h at 60°C. The reaction mixture was allowed to cool to rt, was diluted withEtOAc and washed with water. The org. extracts were dried over MgSO₄,filtered and the solvents were removed under reduced pressure.Purification of the residue by FC (EtOAc/heptane 1:4→3:7) led to thetitle compound (378 mg, 77%). LC-MS: Rt=1.35 min, ES+=488.16.

4-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F4)

Prepared as described for compound F1but from compound E1 (4.7 g, 12.5mmol), 2,3,6-trifluorophenol (3.7 g, 25.0 mmol), azodicarboxyldipiperidide (6.32 g, 34.2 mmol), tributylphosphine (85%, 9.3 mL, 37.6mmol) and toluene (100 mL). Purification of the residue by FC yieldedthe title compound (5.23 g, 83%).

4-{4-[2-(2,3,5-Trimethylphenoxy)ethyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F5)

As described for compound D2 but from compound H1 (3.07 g, 9.63 mmol),BuLi (1.6M in hexane, 6.9 mL, 10.3 mmol), ZnCl₂ (1M in THF, 10.9 mL,10.9 mmol), compound C2 (2.50 g, 6.42 mmol), Pd(PPh₃)₄ (148 mg, 0.128mmol) and THF (50 mL). Purification by FC yielded the title compound(1.77 g, 57%).

4-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (F6)

Prepared as described for compound F1but from compound E2 (1.69 g, 4.4mmol), 2-chloro-4,5-dimethylphenol (1.05 g, 6.6 mmol), azodicarboxyldipiperidide (1.67 g, 6.6 mmol), tributylphosphine (2.2 mL, 8.8 mmol)and toluene (45 mL). Purification of the residue by FC yielded the titlecompound (1.73 g, 76%). LC-MS: Rt=1.38; ES+: 516.24.

Compounds of Type G

4-{1-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G1)

To a sol. of compound F1(742 mg, 1.30 mmol) in EtOH (13 mL) was addedaq. 1M NaOH (13 mL). The resulting mixture was stirred for 35 min at 80°C., then allowed to cool to rt. Aq. 1M HCl (13 mL) was added and theresulting mixture was extracted with EtOAc (3×). The combined org.extracts were dried over MgSO₄, filtered and the solvents were removedunder reduced pressure. Purification of the residue by FC (EtOAc/heptane2:3) led to the title compound (418 mg, 60%). LC-MS: R_(t)=1.32 min,ES+=534.04.

4-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G2)

To a sol. of compound F2 (374 mg, 0.77 mmol) in EtOH (8 mL) was addedaq. 1M NaOH (7.7 mL). The resulting mixture was stirred for 35 min at80° C., then allowed to cool to rt. Aq. 1M HCl (7.7 mL) was added andthe resulting mixture was extracted with EtOAc (3×). The combined org.extracts were dried over MgSO₄, filtered and the solvents were removedunder reduced pressure. Purification of the residue by FC (EtOAc/heptane2:3) led to the title compound (218 mg, 60%). LC-MS: R_(t)=1.29 min,ES+=472.15.

4-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl}-5,6dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G3)

To a sol. of compound F3 (378 mg, 0.77 mmol) in EtOH (8 mL) was addedaq. 1M NaOH (7.7 mL). The resulting mixture was stirred for 35 min at80° C., then allowed to cool to rt. Aq. 1M HCl (7.7 mL) was added andthe resulting mixture was extracted with EtOAc (3×). The combined org.extracts were dried over MgSO₄, filtered and the solvents were removedunder reduced pressure. Purification of the residue by FC (EtOAc/heptane2:3) led to the title compound (220 mg, 60%). LC-MS: R_(t)=1.25 min,ES+=474.17.

4-{1-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G4)

As described for compound G1, but from compound F4 (5.23 g, 10.3 mmol),aq. NaOH (1M, 90 mL) and EtOH (90 mL). The title product was usedfurther without chromatographic purification (4.55 g, 89%).

4-{4-[2-(2,3,5-Trimethylphenoxy)ethyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G5)

As described for compound G1, but from compound F5 (2.17 g, 4.53 mmol),aq. NaOH (1M, 30 mL) and EtOH (30 mL). The title product was usedfurther without chromatographic purification (1.86 g, 89%).

4-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (G6)

As described for compound G1, but from compound F6 (1.73 g, 3.3 mmol),aq. NaOH (1M, 33 mL) and EtOH (33 mL). The title product was usedfurther without chromatographic purification. LC-MS: R_(t)=1.10; ES+:502.31.

2-(4-Bromophenyl)eth-1-yl 2,3,5-trimethylphenyl ether (H1)

A mixture of 2-(4-bromophenyl)ethanol (20.0 mL, 143 mmol),2,3,5-trimethylphenol (31.1 g, 229 mmol), azodicarboxylic dipiperidide(72.1 g, 286 mmol) and tributylphosphine (88 mL; 357 mmol) in toluene(2.00 L) was heated to reflux for 2 h. The mixture was allowed to coolto rt. The mixture was filtered, washed with toluene and the solventswere partially removed under reduced pressure. The residue was dilutedwith Et₂O and washed with aq. 1M NaOH (2×). The org. extracts were driedover MgSO₄, filtered, and the solvents were removed under reducedpressure. Purification of the residue by FC (petroleumether→Et₂O/petroleum ether 1:3) yielded the title compound (33.1 g,73%). LC-MS: R_(t)=6.95.

1-Bromo-4-[3-(2-methoxybenzyloxy)prop-1-yloxy]benzene (K)

4-Bromophenol (4.32 g, 25.0 mmol) and1-(3-chloro-propoxymethyl)-2-methoxy-benzene (Vieira E., et al., Bioorg.Med. Chem. Letters, 1999, 9, 1397) (4.88 g, 22.7 mmoL) were dissolved inDMF (150 mL). NaI (1.50 g, 0.10 mmol) and Cs₂CO₃ (16.3 g, 50.0 mmol)were added. The mixture was heated to 80° C. and stirred for 6 h beforeit was allowed to cool to rt. After dilution with EtOAc (600 mL) themixture was washed with water (1×), aq. 1M NaOH (1×), and aq. 1M HCl(1×). The org. extracts were dried over MgSO₄ and filtered. The solventswere removed under reduced pressure. Purification of the residue by FC(Et2O/petroleum ether 1:9→1:4) yielded the title compound (5.66 g, 71%).R_(f)=0.60 (Et₂O/heptane 1:1). ¹H-NMR (CDCl₃): 7.38-7.34 (m, 3 H); 7.26(t, J=8.7 Hz, 1 H); 6.94 (t, J=8.7 Hz, 1 H); 6.86 (d, J=8.2 Hz, 1 H);6.78 (d, J=9.0 Hz, 2 H); 4.57 (s, 2 H); 4.07 (t, J=6.3 Hz, 2 H); 3.81(s, 3 H); 3.70 (t, J=6.3 Hz, 2 H), 2.10 (quint., J=6.3 Hz, 2 H).

1-Benzyl-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-I,2,5,6-tetrahydro-pyridine-3-carboxylicacid [1-(2-chlorophenyl)ethyl]methylamide (L1)

To a suspension of tetrahydropyridine D1 (2.25 g, 4.26 mmol) in EtOH (50mL) NaOH (1M in water, 30 mL) was added. After 4 h the mixture waswarmed up to 60° C. and stirred for 5 h. The reaction mixture wasallowed to cool to rt and the pH was adjusted to 7 with aq. 1M HCl. Thesolvents were removed under reduced pressure and the residue was driedat high vacuum. The dried residue was triturated with EtOH and filtered(3×), the combined filtrates were evaporated under reduced pressure, andthe residue was dried at high vacuum. The residue was diluted in CHCl₃(20 mL), and [2-(2-chlorophenyl)ethyl]methylamine (Jaques B.; Wallace R.G., Tetrahedron, 1977, 33, 581, 1.48 g, 8.72 mmol), DMAP (cat. amount),HOBt (cat. amount) and EDC.HCl (836 mg, 4.36 mmol) were added. After 4 hat rt the mixture was diluted with CH₂Cl₂ and washed with aq. 10% Na₂CO₃(1×). The org. extracts were dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. Purification of theresidue by FC (EtOAc/heptane 1:4→1:3→2:3→3:2 EtOAc) gave the titlecompound (0.48 g, 17%). R_(f)=0.13 (EtOAcheptane 1:1). LC-MS: R_(t)=4.24min, ES+=639.33.

4-{4-[1-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester (R)

A sol. of compound D3 (17.6 g) in MeOH (400 ml) and IN NaOH-soln. (250ml) was heated at 110° C. for 1.5 h. The mixture was allowed to cool tort and aq. 1M HCl was added to reach pH 4, and was extracted with EtOAc(2×1 50 ml). The org. extracts were dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. A sol. this crude material(14 g), imidazol (9.75 g) and TBDMSCl (13.49 g) in DMF (80 ml) wasstirred at room temperature for 1 h. Aq. sat. NH₄Cl (100 ml) was addedand the mixture was extracted with heptane (3×100 ml). ).The org.extracts were dried over MgSO₄, filtered, and the solvents were removedunder reduced pressure. A sol. of this crude product, and K₂CO₃ (2.5 g)in MeOH (50 ml) and water (50 ml) was stirred at room temperature for 1h. Aq. sat. NH₄Cl (100 ml) was added and the mixture was extracted withEt₂O (3×50 ml). ).The org. extracts were dried over MgSO₄, filtered, andthe solvents were removed under reduced pressure. The crude titleproduct (17.2 g, quant. yield) was used in the next step withoutpurification. LC-MS: R_(t)=1.12; ES+:478.38.

Compounds of Type S

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[(2-chloro3-trifluoromethylbenzyl)cyclopropylcarbamoyl]-3,6-dihydro-2H-pyridin-1-carboxylicacid tert-butyl ester (S1)

A sol. of compound R (2.62 g, 5.5 mmol),(2-chloro-3-trifluoromethylbenzyl)-cyclopropylamine (2.74 g, 11.0 mmol),DMAP (132 mg, 1.12 mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05mmol) and EDC.HCl (1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL) was stirredovernight. The mixture was washed with aq. 1M HCl (3×) and aq. sat.NaHCO₃ (1×). The org. extracts were dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. Purification of theresidue by FC (EtOAc/heptane 1:9→1:4→1:3) yielded the title compound(2.95 g, 75%). R_(f)=0.55 (EtOAc/heptane 1:1). LC-MS: R_(t)=7.68.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(3,5-difluorobenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S2)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),cyclopropyl-(3,5-difluorobenzyl)amine (2.01 g, 11 mmol), DMAP (132 mg,1.12 mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) andEDC.HCl (1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FCyielded the title compound (2.83 g, 79%). LC-MS: R_(t)=1.20; ES+:643.23.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,6-dihydro-2H-pyridin-1-carboxylicacid tert-butyl ester (S3)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),cyclopropyl-(2,3-dichlorobenzyl)amine (2.38 g, 11 mmol), DMAP (132 mg,1.12 mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) andEDC.HCl (1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FCyielded the title compound (2.02 g, 53%). LC-MS: R_(t)=1.20; ES+:675.15.

5-[(2-Bromobenzyl)cyclopropylcarbamoyl]-4-{4-[2-(tert-butyldimethyl-silanyloxy)ethoxy]phenyl}-3,6-dihydro-2Hi-pyridine-1-carboxylicacid tert-butyl ester (S4)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),(2-bromobenzyl)cyclopropylamine (2.49 g, 11 mmol), DMAP (132 mg, 1.12mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) and EDC.HCl(1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FC yielded thetitle compound (2.02 g, 53%). LC-MS: R_(t)=1.26; ES+: 687.41.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(2,3-dimethylbenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S5)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),cyclopropyl-(2,3-dimethylbenzyl-amine (1.93 g, 11 mmol), DMAP (132 mg,1.12 mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) andEDC.HCl (1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FCyielded the title compound (2.25 g, 64%). LC-MS: R_(t)=1.26; ES+:635.53.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-3-trifluoromethoxybenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S6)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),cyclopropyl-(3-trifluoromethoxybenzyl)amine (2.54 g, 11 mmol), DMAP (132mg, 1.12 mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) andEDC.HCl (1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FCyielded the title compound (2.51 g, 66%). LC-MS: R_(t)=1.26; ES+:691.48.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(3-methylbenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S7)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),cyclopropyl-(3-methylbenzyl)amine (1.77 g, 11 mmol), DMAP (132 mg, 1.12mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) and EDC.HCl(1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FC yielded thetitle compound (2.14 g, 62%). LC-MS: R_(t)=1.25; ES+: 621.54.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5[(3-chlorobenzyl)-cyclopropylcarbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S8)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),(3-chlorobenzyl)cyclopropylamine (1.99 g, 11 mmol), DMAP (132 mg, 1.12mmol), DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) and EDC.HCl(1.58 g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FC yielded thetitle compound (2.44 g, 69%). LC-MS: R_(t)=1.26; ES+: 641.44.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[(2-chlorobenzyl)-ethylcarbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S9)

As described for compound S1, but from compound R (2.62 g, 5.5 mmol),(2-chlorobenzyl)ethylamine (1.87 g, 11 mmol), DMAP (132 mg, 1.12 mmol),DIPEA (3.67 mL, 22.0 mmol), HOBt (817 mg, 6.05 mmol) and EDC.HCl (1.58g, 8.25 mmol) in CH₂Cl₂ (70 mL). Purification by FC yielded the titlecompound (2.31 g, 67%). LC-MS: R_(t)=1.25; ES+: 629.45.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(2-fluoro-5-methoxybenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S10)

As described for compound S1, but from compound R (2.59 g, 5.42 mmol),cyclopropyl-(2-fluoro-5-methoxybenzyl)amine (2.12 g, 10.8 mmol), DMAP(132 mg, 1.12 mmol), DIPEA (3.70 mL, 21.7 mmol), HOBt (732 mg, 5.42mmol) and EDC.HCl (1.56 g, 8.13 mmol) in CH₂Cl₂ (50 mL). Purification byFC yielded the title compound (2.21 g, 62%).

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl})-[(6-chlorobenzo[1,3-dioxol-5-ylmethyl)cyclopropylcarbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S11)

As described for compound S1, but from compound R (2.41 g, 5.05 mmol),(6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamine (2.28 g, 10.1mmol), DMAP (123 mg, 1.01 mmol), DIPEA (3.50 mL, 20.2 mmol), HOBt (682mg, 5.05 mmol) and EDC.HCl (1.45 g, 7.58 mmol) in CH₂Cl₂ (50 mL).Purification by FC yielded the title compound (1.97 g, 57%).

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-3,5-dimethoxybenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S12)

As described for compound S1, but from compound R (2.80 g, 5.86 mmol),cyclopropyl-(3,5-dimethoxybenzyl)amine (2.43 g, 11.7 mmol), DMAP (143mg, 1.17 mmol), DIPEA (3.00 mL, 17.6 mmol), HOBt (792 mg, 5.86 mmol) andEDC.HCl (1.68 g, 8.79 mmol) in CH₂Cl₂ (50 mL). Purification by FCyielded the title compound (2.97 g, 76%). LC-MS: R_(t)=1.23; ES+=667.1.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(3-methoxybenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S13)

As described for compound S1, but from compound R (2.80 g, 5.86 mmol),cyclopropyl-(3-methoxybenzyl)amine (2.08 g, 11.7 mmol), DMAP (143 mg,1.17 mmol), DIPEA (3.00 mL, 17.6 mmol), HOBt (792 mg, 5.86 mmol) andEDC.HCl (1.68 g, 8.79 mmol) in CH₂Cl₂ (50 mL). Puritication by FCyielded the title compound (2.68 g, 72%). LC-MS: R_(t)=1.23; ES+=637.3.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[cyclopropyl-(3,4-dimethoxybenzyl)carbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S14)

As described for compound S1, but from compound R (2.48 g, 5.19 mmol),cyclopropyl-(3,4-dimethoxybenzyl)amine (2.15 g, 10.4 mmol), DMAP (127mg, 1.04 mmol), DIPEA (3.60 mL, 20.8 mmol), HOBt (700 mg, 5.19 mmol) andEDC.HCl (1.49 g, 7.79 mmol) in CH₂Cl₂ (50 mL). Purification by FCyielded the title compound (2.92 g, 84%). LC-MS: R_(t)=1.23; ES+=637.3.

4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5-[(2-chlorobenzyl)-cyclopropylcarbamoyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (S15)

As described for compound S1, but from compound R (3.82 g, 8.00 mmol),(2-chlorobenzyl)cyclopropylamine (4.36 g, 24.0 mmol), DMAP (195 mg, 1.60mmol), DIPEA (5.50 mL, 32.0 mmol), HOBt (1.08 g, 8.00 mmol) and EDC.HCl(2.30 g, 12.0 mmol) in CH₂Cl₂ (70 mL). Purification by FC yielded thetitle compound (3.10 g, 60%). LC-MS: R_(t)=1.26; ES+=641.4.

Compounds of Type T

5-[(2-Chloro-3-trifluoromethylbenzyl)cyclopropylcarbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T1)

A sol. of compound S1 (2.95 g, 4.16 mmol) and TBAF (1M in THF, 6.24 mL,6.24 mmol) in THF (15 mL) was stirred at rt for 90 min. The mixture wasdiluted with EtOAc and washed with brine (1×), water (1×) and brineagain (1×). The org. extracts were dried over MgSO₄, filtered, and thesolvents were removed under reduced pressure. Purification of theresidue by FC (EtOAc/heptane 1:4→2:3→3:2→4:1) yielded the title compound(1.56 g, 63%). R_(f)=0.10 (EtOAc/heptane 1:1) were collected. LC-MS:R_(t)=5.63; ES+=595.37.

5-[Cyclopropyl-(3,5-difluorobenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T2)

As described for compound T1, but from compound S2 (2.83 g, 4.40 mmol),TBAF (1M in THF, 6.60 mL, 6.60 mmol) and THF (15 mL). Purification by FCyielded the title compound (0.95 g, 41%). LC-MS: R_(t)=5.16; ES+=529.48.

5-[Cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T3)

As described for compound T1, but from compound S3 (2.47 g, 3.66 mmol),TBAF (1M in THF, 5.48 mL, 5.48 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.43 g, 70%). LC-MS: R_(t)=5.52; ES+=561.31.

5-1(2-Bromobenzyl)cyclopropylcarbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T4)

As described for compound T1, but from compound S4 (2.02 g, 2.95 mmol),TBAF (1M in THF, 4.42 mL, 4.42 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.40 g, 83%). LC-MS: R_(t)=5.22; ES+=571.32.

5-[Cyclopropyl-(2,3-dimethylbenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T5)

As described for compound T1, but from compound S5 (2.25 g, 3.54 mmol),TBAF (1M in THF, 5.32 mL, 5.32 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.74 g, 94%). LC-MS: R_(t)=5.32; ES+=521.68.

5-[Cyclopropyl-(3-trifluoromethoxybenzyl)carbamoyl]-4-[4-(2-hydroxy-ethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T6)

As described for compound T1, but from compound S6 (2.51 g, 3.63 mmol),TBAF (1M in THF, 5.45 mL, 5.45 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.94 g, 93%). LC-MS: R_(t)=1.04; ES+=577.32.

5-[Cyclopropyl-(3-methylbenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T7)

As described for compound T1, but from compound S7 (2.14 g, 3.45 mmol),TBAF (1M in THF, 5.20 mL, 5.20 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.66 g, 95%). LC-MS: R_(t)=5.19; ES+=507.58.

5-[(3-Chlorobenzyl)cyclopropylcarbamoyl]4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T8)

As described for compound T1, but from compound S8 (2.44 g, 3.80 mmol),TBAF (1M in THF, 5.70 mL, 5.70 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.71 g, 85%). LC-MS: R_(t)=5.25; ES+=527.37.

5-[(2-Chlorobenzyl)ethylcarbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T9)

As described for compound T1, but from compound S9 (2.31 g, 3.67 mmol),TBAF (1M in THF, 5.50 mL, 5.50 mmol) and THF (15 mL). Purification by FCyielded the title compound (1.40 g, 74%). LC-MS: R_(t)=5.19; ES+=559.06.

5-[Cyclopropyl-(2-fluoro-5-methoxybenzyl)carbamoyl]-4-[4-(2-hydroxy-ethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T10)

As described for compound T1, but from compound S10 (1.97 g, 2.87 mmol),TBAF (1M in THF, 5.75 mL, 5.75 mmol) and THF (20 mL). Purification by FCyielded the title compound (1.50 g, 97%). LC-MS: R_(t)=5.02; ES+=541.46.

5-[(6-Chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylcarbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T11)

As described for compound T1, but from compound S11 (2.20 g, 3.37 mmol),TBAF (1M in THF, 6.75 mL, 6.75 mmol) and THF (25 mL). Purification by FCyielded the title compound (1.58 g, 82%). LC-MS: R_(t)=5.28; ES+=571.34.

5-[Cyclopropyl-(3,5-dimethoxybenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T12)

As described for compound T1, but from compound S12 (2.97 g, 4.45 mmol),TBAF (1M in THF, 8.90 mL, 8.90 mmol) and THF (30 mL). Purification by FCyielded the title compound (2.14 g, 87%). LC-MS: R_(t)=0.99; ES+=553.2.

5-[Cyclopropyl-(3-methoxybenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T13)

As described for compound T1, but from compound S13 (2.68 g, 4.21 mmol),TBAF (1M in THF, 8.40 mL, 8.40 mmol) and THF (30 mL). Purification by FCyielded the title compound (2.03 g, 92%). LC-MS: R_(t)=0.97; ES+=523.2.

5-[Cyclopropyl-(3,4-dimethoxybenzyl)carbamoyl]-4-[4-(2-hydroxyethoxy)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T14)

As described for compound T1, but from compound S14 (2.92 g, 4.38 mmol),TBAF (1M in THF, 8.80 mL, 8.80 mmol) and THF (30 mL). Purification by FCyielded the title compound (2.02 g, 83%). LC-MS: R_(t)=0.96; ES+=553.21.

5-[(2-Chlorobenzyl)cyclopropylcarbamoyl]-4-[4-(2-hydroxyethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (T15)

As described for compound T1, but from compound S15 (3.10 g, 4.84 mmol),TBAF (1M in THF, 10.3 mL, 10.3 mmol) and THF (40 mL). Purification by FCyielded the title compound (2.35 g, 92%). LC-MS: R_(t)=1.02; ES+=527.14.

Preparation of the Final Compounds

Example 14-{4-[3-(2-Methoxybenzyloxy)propoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide trifluoroacetate salt

To a sol. of tetrahydropyridine L1 (410 mg, 0.641 mmol) in CH₂ClCH₂Cl(10 mL) at rt ClCO₂CHClCH₃ (0.350 mL, 3.21 mmol) was added. The sol. wasstirred at rt for 1 h, then heated to reflux. After 5 h another portionof ClCO₂CHClCH₃ (0.350 mL, 3.21 mmol) was added. After 1 h the solventswere removed under reduced pressure, and the residue was diluted withMeOH (5 mL) and water (5 mL). The mixture was stirred overnight and thesolvents were partially removed under reduced pressure. The residue wasdiluted with EtOAc and the mixture was washed with aq. 1M NaOH (1×). Theorg. extracts were dried over MgSO₄, filtered, and the solvents wereremoved under reduced pressure. Purification of the residue by HPLC(H₂O, MeOH, TFA) yielded the title compound (31 mg). LC-MS: R_(t)=3.98min, ES+=593.13.

Example 24-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and [2-(2-chlorophenyl)ethyl]methylamine (Jaques, B.; Wallace, R. G.,Tetrahedron, 1977, 33, 581). LC-MS: R_(t)=1.04 min, ES+=586.96.

Example 34-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid 2-phenethylmethylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and methylphenethylamine. LC-MS: R_(t)=1.01 min, ES+=553.01.

Example 44-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)methylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and (2-chlorobenzyl)methylamine (Holzgrabe, U.; Arch. Pharm (Weinheim,Ger.), 1987, 320, 647). LC-MS: R_(t)=1.03 min, ES+=572.95.

Example 54-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=1.07 min, ES+=598.98.

Example 64-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide formate salt

According to the general procedures A and B, starting from compound G2and [2-(2-chlorophenyl)ethyl]methylamine (Jaques, B.; Wallace, R. G.,Tetrahedron, 1977, 33, 581). LC-MS: R_(t)=0.99 min, ES+=523.02.

Example 74-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid 2-phenethylmethylamide formate salt

According to the general procedures A and B, starting from compound G2and methylphenethylamine. LC-MS: R_(t)=0.96 min, ES+=489.07.

Example 84-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)methylamide formate salt

According to the general procedures A and B, starting from compound G2and (2-chlorobenzyl)methylamine (Holzgrabe, U.; Arch. Pharm (Weinheim,Ger.), 1987, 320, 647). LC-MS: R_(t)=0.98 min, ES+=509.01.

Example 94-{4-[3-(2-Chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G2and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=1.02 min, ES+=535.06.

Example 104-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide formate salt

According to the general procedures A and B, starting from compound G3and [2-(2-chlorophenyl)ethyl]methylamine (Jaques, B.; Wallace, R. G.,Tetrahedron, 1977, 33, 581). LC-MS: R_(t)=0.97 min, ES+=525.03.

Example 114-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid 2-phenethylmethylamide formate salt

According to the general procedures A and B, starting from compound G3and methylphenethylamine. LC-MS: R_(t)=0.94 min, ES+=491.10.

Example 124-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl)}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)methylamide formate salt

According to the general procedures A and B, starting from compound G3and (2-chlorobenzyl)methylamine (Holzgrabe, U.; Arch. Pharm. (Weinheim,Ger.), 1987, 320, 647). LC-MS: R_(t)=0.96 min, ES+=511.01.

Example 134-{4-[3-(2,5-Difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G3and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=1.00 min, ES+=537.03.

Example 144-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=1.07 min, ES+=598.98.

Example 154-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=1.03 min, ES+=555.17.

Example 164-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl)}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and (2-chlorobenzyl)ethylamine. LC-MS: R_(t)=1.01 min, ES+=543.16.

Example 174-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluorobenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2-fluorobenzyl)amine. LC-MS: R_(t)=1.01 min,ES+=539.14.

Example 184-{4-[3-(2,3,6Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethoxybenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3-trifluoromethoxybenzyl)amine. LC-MS: R_(t)=1.04 min,ES+=589.14.

Example 194-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2-methylbenzyl)amine. LC-MS: R_(t)=1.03 min,ES+=535.17.

Example 204-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amine. LC-MS: R_(t)=1.00 min,ES+=581.33.

Example 214-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(3-methoxyphenoxy)ethyl]amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-[2-(3-methoxyphenoxy)ethyl]amine. LC-MS: R_(t)=1.02 min,ES+=581.34.

Example 224-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-m-tolyloxyethyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2-m-tolyloxyethyl)amine. LC-MS: R_(t)=1.05 min,ES+=565.31.

Example 234-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]cyclopropylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and [2-(2-chlorophenyl)ethyl]cyclopropylamine. LC-MS: R_(t)=0.93 min,ES+=569.41.

Example 244-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-fluorophenyl)ethyl]amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-[2-(4-fluorophenyl)ethyl]amine. LC-MS: R_(t)=0.92 min,ES+=553.51.

Example 254-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-o-tolylethyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2-o-tolylethyl)amine. LC-MS: R_(t)=0.93 min,ES+=549.47.

Example 264-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3,5-dimethoxybenzyl)amine. LC-MS: R_(t)=0.91 min,ES+=581.48.

Example 274-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-p-tolylethyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl(2-p-tolylethyl)amine. LC-MS: R_(t)=0.93 min, ES+=549.53.

Example 284-{4-[2-(2,3,5-Trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethylbenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G5and cyclopropyl-(3-trifluoromethylbenzyl)amine LC-MS: R_(t)=0.96 min,ES+=563.46.

Example 294-{4-[2-(2,3,5-Trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G5and cyclopropyl-(2-methylbenzyl)amine. LC-MS: R_(t)=0.94 min,ES+=509.50.

Example 304-{4-[2-(2,3,5-Trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropylphenethylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G5and cyclopropylphenethylamine. LC-MS: R_(t)=0.94 min, ES+=509.53.

Example 314-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and (2-chlorobenzyl)ethylamine. LC-MS: R_(t)=0.92 min, ES+=587.13.

Example 324-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and cyclopropyl-(2-methylbenzyl)amine. LC-MS: R_(t)=0.92 min,ES+=577.20.

Example 334-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amine. LC-MS: R_(t)=0.91 min,ES+=623.21.

Example 344-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropylphenethylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and cyclopropylphenethylamine. LC-MS: R_(t)=0.92 min, ES+=577.19.

Example 354-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-o-tolylethyl)amide

According to the general procedures A and B, starting from compound G1and cyclopropyl-(2-o-tolylethyl)amine. LC-MS: R_(t)=0.93 min,ES+=593.19.

Example 364-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and cyclopropyl-(3,5-dimethoxybenzyl)amine. LC-MS: R_(t)=0.90 min,ES+=623.38.

Example 374-{4-[3-(2-Bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-p-tolylethyl)amide trifluoroacetate salt

According to the general procedures A and B, starting from compound G1and cyclopropyl-(2-p-tolylethyl)amine. LC-MS: R_(t)=0.95 min,ES+=591.38.

Example 384-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide trifluoroacetate salt

According to the general procedures A and B, starting from compound G6and (2-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=0.92 min, ES+=577.20.

Example 394-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2-fluoro-5-methoxybenzyl)amine. LC-MS: R_(t)=0.91 min,ES+=569.16.

Example 404-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3-methoxybenzyl)amine. LC-MS: R_(t)=0.91 min,ES+=551.17.

Example 414-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,4-dimethoxybenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3,4-dimethoxybenzyl)amine. LC-MS: R_(t)=0.88 min,ES+=581.18.

Example 424-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G4and (2-chloro-3-trifluoromethylbenzyl)cyclopropylamine. LC-MS:R_(t)=0.96 min, ES+=623.07.

Example 434-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G4and (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamine. LC-MS:R_(t)=0.93 min, ES+=599.08.

Example 444-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-6-fluorobenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G4and (2-chloro-6-fluorobenzyl)-cyclopropylamine. LC-MS: R_(t)=0.92 min,ES+=573.10.

Example 454-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G4and (2-bromobenzyl)cyclopropylamine. LC-MS: R_(t)=0.94 min, ES+=601.04.

Example 464-{4-[3-(2,3,6Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2,3-dimethylbenzyl)amine. LC-MS: R_(t)=0.94 min,ES+=549.17.

Example 474-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-fluoro-2-methylbenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3-fluoro-2-methylbenzyl)amine. LC-MS: R_(t)=0.93 min,ES+=553.17.

Example 484-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2,3-dichlorobenzyl)amine. LC-MS: R_(t)=0.95 min,ES+=589.07.

Example 494-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(3-methylbenzyl)amine. LC-MS: R_(t)=0.93 min,ES+=535.19.

Example 504-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-difluorobenzyl)amide formate salt

According to the general procedures A and B, starting from compound G4and cyclopropyl-(2,3-difluorobenzyl)amine. LC-MS: R_(t)=0.92 min,ES+=557.15.

Example 514-{4-[3-(2,3,6-Trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures A and B, starting from compound G4and (3-chlorobenzyl)cyclopropylamine. LC-MS: R_(t)=0.93 min, ES+=555.07.

Example 524-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.97 min, ES+=620.90.

Example 534-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1(50 mg) and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.98 min,ES+=653.03.

Example 544-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.96 min, ES+=579.12.

Example 554-{4-[2-(2,3,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 2,3,6-trifluorophenol. LC-MS: R_(t)=0.94 min, ES+=625.20.

Example 564-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.94 min, ES+=635.19.

Example 574-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.93 min, ES+=591.16.

Example 584-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.95 min, ES+=625.21.

Example 594-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.96 min, ES+=601.03.

Example 604-{4-[2-(2,3,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,3,6-trifluorophenol. LC-MS: R_(t)=0.92 min, ES+=591.01.

Example 614-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.96 min, ES+=659.17.

Example 624-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.94 min, ES+=625.19.

Example 634-{4-[2-(2,6-Difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,6-difluoro-3-methylphenol. LC-MS: R_(t)=0.94 min, ES+=587.14.

Example 644-{4-[2-(4-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide

According to the general procedures F and B, starting from compound T3and 4-chloro-2-methoxyphenol. LC-MS: R_(t)=0.93 min, ES+=601.18.

Example 654-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.95 min, ES+=629.05.

Example 664-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.95 min, ES+=630.94

Example 674-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T7and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.95 min, ES+=656.12.

Example 684-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.93 min, ES+=611.04.

Example 694-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T8and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.95 min, ES+=587.03.

Example 704-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.94 min, ES+=583.26.

Example 714-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.97 min, ES+=633.11.

Example 724-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide formate salt

According to the general procedures F and B, starting from compound T9and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.94 min, ES+=573.07.

Example 734-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T13and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.93 min, ES+=581.09.

Example 744-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 3-chloro-2,6-difluorophenol. LC-MS: R_(t)=0.93 min, ES+=567.24.

Example 754-{4-[2-(Benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and benzo[1,3]dioxol-5-ol. LC-MS: R_(t)=0.94 min, ES+=625.19.

Example 764-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T6and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.97 min, ESP+=653.12.

Example 774-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-difluorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T2and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.93 min, ES+=593.24.

Example 784-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,4-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T14and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.90 min, ES+=611.06.

Example 794-{4-(2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.91 min, ES+=551.30.

Example 804-{4-[2-(2-Bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2-bromo-5-fluorophenol. LC-MS: R_(t)=0.91 min, ES+=551.30.

Example 814-{4-[2-(2,3,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,3,6-trifluorophenol. LC-MS: R_(t)=0.91 min, ES+=551.12.

Example 824-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 3-chloro-2,6-trifluorophenol. LC-MS: R_(t)=0.94 min, ES+=607.14.

Example 834-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.91 min, ES+=601.15.

Example 844-{4-[2-(2-Bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 2-bromo-5-fluorophenol. LC-MS: R_(t)=0.95 min, ES+-669.20.

Example 854-{4-[2-(Benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and benzo[1,3]dioxol-5-ol. LC-MS: R_(t)=0.90 min, ES+=581.17.

Example 864-{4-[2-(4-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 4-chloro-2-methoxyphenol. LC-MS: R_(t)=0.94 min, ES+=635.16.

Example 874-{4-[2-(4-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 4-chloro-2-methoxyphenol 1. LC-MS: R_(t)=0.92 min, ES+=561.29.

Example 884-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.94 min, ES+=599.03.

Example 894-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,5-dichlorophenol. LC-MS: R_(t)=0.95 min, ES+=607.20.

Example 904-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide

According to the general procedures F and B, starting from compound T5and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.95 min, ES+=559.18.

Example 914-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.98 min, ES+=673.24.

Example 924-{4-[2-(2,6-Difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 2,6-difluoro-3-methylphenol. LC-MS: R_(t)=0.95 min, ES+=621.31.

Example 934-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)-amide formate salt

According to the general procedures F and B, starting from compound T5and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.96 min, ES+=599.30.

Example 944-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 2,5-dichlorophenol. LC-MS: R_(t)=0.96 min, ES+=641.12.

Example 954-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,5-dichlorophenol. LC-MS: R_(t)=0.94 min, ES+=565.23.

Example 964-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2-chloro-4-trifluoromethylphenol phenol. LC-MS: R_(t)=0.97 min,ES+=639.14.

Example 974-{4-[2-(2-Bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2-bromo-5-fluorophenol. LC-MS: R_(t)=0.94 min, ES+=634.92.

Example 984-{4-[2-(2,3-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2,3-dichlorophenol. LC-MS: R_(t)=0.94 min, ES+=607.19.

Example 994-{4-[2-(2-Chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 2-chloro-5-fluorophenol. LC-MS: R_(t)=0.93 min, ES+=591.21.

Example 1004-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,5-dichlorophenol. LC-MS: R_(t)=0.94 min, ES+=617.11.

Example 1014-{4-[2-(4-Chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T3and 4-chloro-2-methylphenol. LC-MS: R_(t)=0.95 min, ES+=587.22.

Example 1024-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T6and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.95 min, ES+=639.22.

Example 1034-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.89 min, ES+=571.24.

Example 1044-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.92 min, ES+=615.27.

Example 1054-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.93 min, ES+=579.15.

Example 1064-{4-[2-(5-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 4-chloro-2-methoxyphenol. LC-MS: R_(t)=0.91 min, ES+=613.21.

Example 1074-{4-[2-(2,3,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,3,6-trifluorophenol. LC-MS: R_(t)=0.91 min, ES+=601.09.

Example 1084-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.93 min, ES+=591.18.

Example 1094-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.95 min, ES+=611.09.

Example 1104-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T8and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.93 min, ES+=589.27.

Example 1114-{4-[2-(2,6-Difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,6-difluoro-3-methylphenol. LC-MS: R_(t)=0.92 min, ES+=547.37.

Example 1124-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.92 min, ES+=603.24.

Example 1134-{4-[2-(2,6-Difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2,6-difluoro-3-methylphenol. LC-MS: R_(t)=0.92 min, ES+=599.21.

Example 1144-{4-[2-(2-Fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 4-chloro-2-methylphenol. LC-MS: R_(t)=0.96 min, ES+=619.23.

Example 1154-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.91 min, ES+=601.19.

Example 1164-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 2,6-difluoro-3-chlorophenol. LC-MS: R_(t)=0.92 min, ES+=617.19.

Example 1174-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-difluorobenzyl)amide formate salt

According to the general procedures F and B, starting from compound T2and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.94 min, ES+=587.14.

Example 1184-{4-[2-(2,4,5-Trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T1and 2,4,5-trichlorophenol. LC-MS: R_(t)=0.98 min, ES+=675.22.

Example 1194-{4-[2-(2-Chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropyl-amide formate salt

According to the general procedures F and B, starting from compound T1and 2-chloro-5-fluorophenol. LC-MS: R_(t)=0.94 min, ES+=623.29.

Example 1204-{4-[2-(2,3-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,3-dichlorophenol. LC-MS: R_(t)=0.93 min, ES+=565.28.

Example 1214-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide formate salt

According to the general procedures F and B, starting from compound T9and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.93 min, ES+=579.15.

Example 1224-{4-[2-(2,4,5-Trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and 2,4,5-trichlorophenol. LC-MS: R_(t)=0.96 min, ES+=599.32.

Example 1234-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 3-chloro-2,3-difluorophenol. LC-MS: R_(t)=0.93 min, ES+=619.11.

Example 1244-{4-[2-(Benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T5and benzo[1,3]dioxol-5-ol. LC-MS: R_(t)=0.89 min, ES+=541.32.

Example 1254-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)-amide formate salt

According to the general procedures F and B, starting from compound T12and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.94 min, ES+=631.27.

Example 1264-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.89 min, ES+=583.24.

Example 1274-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide formate salt

According to the general procedures F and B, starting from compound T9and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.90 min, ES+=545.24.

Example 1284-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxy-benzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.94 min, ES+=619.26.

Example 1294-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.94 min, ES+=633.25.

Example 1304-{4-[2-(4-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T13and 4-chloro-2-methoxyphenol. LC-MS: R_(t)=0.89 min, ES+=563.26

Example 1314-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.96 min, ES+=651.16.

Example 1324-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T13and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.93 min, ES+=601.26.

Example 1334-{4-[2-(2,3,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide formate salt

According to the general procedures F and B, starting from compound T9and 2,3,6-trifluorophenol. LC-MS: R_(t)=0.90 min, ES+=545.04.

Example 1344-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T10and 2,6-difluoro-3-chlorophenol. LC-MS: R_(t)=0.91 min, ES+=587.21.

Example 1354-{4-[2-(2-Bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12(50 mg) and 2-bromo-5-fluorophenol. LC-MS: R_(t)=0.90 min, ES+=613.03.

Example 1364-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T12and 2,5-dichlorophenol. LC-MS: R_(t)=0.92 min, ES+=597.23.

Example 1374-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide formate salt

According to the general procedures F and B, starting from compound T13and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.92 min, ES+=561.14.

Example 1384-{4-[2-(4-Chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide formate salt

According to the general procedures F and B, starting from compound T4and 4-chloro-2-methylphenol. LC-MS: R_(t)=0.94 min, ES+=597.20.

Example 1394-{4-[2-(4-Chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 4-chloro-2-methoxyphenol. LC-MS: R_(t)=0.91 min, ES+=611.23.

Example 1404-{4-[2-(2-Bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T4and 2-bromo-4-fluorophenol. LC-MS: R_(t)=0.92 min. ES+=645.08.

Example 1414-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide

According to the general procedures F and B, starting from compound T13and 2,6-difluoro-3-chlorophenol. LC-MS: R_(t)=0.90 min, ES+=569.23.

Example 1424-{4-[2-(2-Chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T11and 2-chloro-4-trifluoromethylphenol. LC-MS: R_(t)=0.95 min, ES+=649.22.

Example 1434-{4-[2-(2-Chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2-chloro-4,5-dimethylphenol. LC-MS: R_(t)=0.94 min, ES+=565.28.

Example 1444-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,6-dichloro-4-methylphenol. LC-MS: R_(t)=0.95 min, ES+=587.22.

Example 1454-{4-[2-(2,4,5-Trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,4,5-trichlorophenol. LC-MS: R_(t)=0.95 min, ES+=607.19.

Example 1464-{4-[2-(2-Chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2-chloro-5-fluorophenol. LC-MS: R_(t)=0.91 min, ES+=555.26.

Example 1474-{4-[2-(2-Chloro-3,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2-chloro-3,6-difluorophenol. LC-MS: R_(t)=0.91 min, ES+=573.21.

Example 1484-{4-[2-(2-Chloro-6-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2-chloro-6-methylphenol. LC-MS: R_(t)=0.92 min, ES+=551.30.

Example 1494-{4-[2-(2,3-Dichlorophenoxy)ethoxy]phenyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,3-dichlorophenol. LC-MS: R_(t)=0.92 min, ES+=571.21.

Example 1504-{4-[2-(2,6-Dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,6-dichloro-4-fluorophenol. LC-MS: R_(t)=0.93 min, ES+=589.20.

Example 1514-{4-[2-(3-Chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 3-chloro-2,6-difluorophenol. LC-MS: R_(t)=0.91 min, ES+=573.24.

Example 1524-{4-[2-(2,4,6-Trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,4,6-trifluorophenol. LC-MS: R_(t)=0.90 min, ES+=557.28.

Example 1534-{4-[2-(2,5-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,5-dichlorophenol. LC-MS: R_(t)=0.93 min, ES+=573.21.

Example 1544-{4-[2-(2,6-Dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide formate salt

According to the general procedures F and B, starting from compound T15and 2,6-dichlorophenol. LC-MS: R_(t)=0.92 min, ES+=573.20.

The following assay was carried out in order to determine the activityof the compounds of general formula I and their salts.

Inhibition of Human Recombinant Renin by the Compounds of the Invention

The enzymatic in vitro assay was performed in 384-well polypropyleneplates (Nunc). The assay buffer consisted of 10 mM PBS (Gibco BRL)including 1 mM EDTA and 0.1% BSA. The incubates were composed of 50 μLper well of an enzyme mix and 2.5 μL of renin inhibitors in DMSO. Theenzyme mix was premixed at 4° C. and consists of the followingcomponents:

human recombinant renin (0.16 ng/mL)

synthetic human angiotensin(1-14) (0.5 μM)

hydroxyquinoline sulfate (1 mM)

The mixtures were then incubated at 37° C. for 3 h.

To determine the enzymatic activity and its inhibition, the accumulatedAng I was detected by an enzyme immunoassay (EIA) in 384-well plates(Nunc). 5 μL of the incubates or standards were transferred to immunoplates which were previously coated with a covalent complex of Ang I andbovine serum albumin (Ang I-BSA). 75 μL of Ang I-antibodies in assaybuffer above including 0.01% Tween 20 were added and a primaryincubation made at 4° C. overnight. The plates were washed 3 times withPBS including 0.01% Tween 20, and then incubated for 2 h at rt with anantirabbit-peroxidase coupled antibody (WA 934, Amersham). After washingthe plates 3 times, the peroxidase substrate ABTS(2.2′-azino-di-(3-ethyl-benzthiazolinsulfonate), was added and theplates incubated for 60 min at rt. After stopping the reaction with 0.1M citric acid pH 4.3 the plate was evaluated in a microplate reader at405 nm. The percentage of inhibition was calculated of eachconcentration point and the concentration of renin inhibition wasdetermined that inhibited the enzyme activity by 50% (IC₅₀). TheIC₅₀-values of all compounds tested are below 100 nM. However selectedcompounds exhibit a very good bioavailibility and are metabolically morestable than prior art compounds.

1. A compound of the general formula I

wherein X and W represent independently a nitrogen atom or a —CH— group;V represents —(CH₂)_(r)—; -A-(CH₂)_(s)—; —CH₂-A-(CH₂)_(t)—;—(CH₂)_(s)-A-; —(CH₂)₂-A-(CH₂)_(u)—; -A-(CH₂)_(v)—B—;—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—B—;—CH₂—CH₂—CH₂-A-CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂-A-CH₂—; -A-CH₂—CH₂—B—CH₂-CH₂—;—CH₂-A-CH₂—CH₂—B—CH₂—; —CH₂-A-CH₂—CH₂—CH₂—B—; —CH₂—CH₂-A-CH₂—CH₂—B—; Aand B independently represent —O—; —S—; —SO—; —SO₂—; U represents aryl;heteroaryl; T represents —CONR¹—; —(CH₂)_(p)OCO—; —(CH₂)_(p)N(R¹)CO—;—(CH₂)_(p)N(R¹)SO₂—; —COO—; —(CH₂)_(P)OCONR¹; —(CH₂)_(P)N(R^(1′))CONR¹—;Q represents lower alkylene; lower alkenylene; M represents hydrogen;cycloalkyl; aryl; heterocyclyl; heteroaryl; R¹ and R^(1′) independentlyrepresent hydrogen; lower alkyl; lower alkenyl; lower alkinyl;cycloalkyl; aryl; cycloalkyl-lower alkyl; p is the integer1, 2, 3 or 4;r is the integer 3, 4, 5, or 6; s is the integer 2, 3, 4, or 5; t is theinteger 1, 2, 3, or 4; u is the integer 1, 2, or 3; and v is the integer2, 3, or 4; and optically pure enantiomers, mixtures of enantiomers,diastereomers, mixtures of diastereomers, diastereomeric racemates,mixtures of diastereomeric racemates, and the meso-form; andpharmaceutically acceptable salts, solvent complexes and morphologicalforms, of said compound.
 2. The compound of claim 1, wherein Trepresents —CONR¹—; Q represents methylene; and M represents hydrogen;aryl or heteroaryl; and optically pure enantiomers, mixtures ofenantiomers, diastereomers, mixtures of diastereomers, diastereomericracemates, mixtures of diastereomeric racemates, and the meso-form; andpharmaceutically acceptable salts, solvent complexes and morphologicalforms, of said compound.
 3. The compound of claim 1, wherein Vrepresents —CH₂CH₂O—;—CH₂CH₂CH₂O—; —OCH₂CH₂O—; and optically pureenantiomers, mixtures of enantiomers, diastereomers, mixtures ofdiastereomers, diastereomeric racemates, mixtures of diastereomericracemates, and the meso-form; and pharmaceutically acceptable salts,solvent complexes and morphological forms, of said compound.
 4. Thecompound of claim 1, wherein X and W represent —CH—; and optically pureenantiomers, mixtures of enantiomers, diastereomers, mixtures ofdiastereomers, diastereomeric racemates, mixtures of diastereomericracemates, and the meso-form; pharmaceutically acceptable salts, solventcomplexes and morphological forms, and said compound.
 5. The compound ofclaim 1, wherein U represents a mono-, di-, or trisubstituted phenyl andthe substituents are independently halogen, lower alkyl, lower alkoxy,trifluoromethyl, trifluoromethoxy; and optically pure enantiomers,mixtures of enantiomers, diastereomers, mixtures of diastereomers,diastereomeric racemates, mixtures of diastereomeric racemates, and themeso-form; and pharmaceutically acceptable salts, solvent complexes andmorphological forms, of said compound.
 6. A compound selected from thegroup consisting of4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylicacid 2-phenethylmethylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylicacid (2-chlorobenzyl)methylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridi-ne-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide;4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid 2-phenethylmethylamide;4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)methylamide;4-{4-[3-(2-chlorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]methylamide;4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid 2-phenethylmethylamide;4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)methylamide;4-{4-[3-(2,5-difluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluorobenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethylbenzyll)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(3-methoxyphenoxy)ethyl]amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-m-tolyloxyethyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid [2-(2-chlorophenyl)ethyl]cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-fluorophenyl)ethyl]amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-o-tolylethyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-p-tolylethyl)amide;4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethylbenzyl)amide;4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide;4-{4-[2-(2,3,5-trimethylphenoxy)ethyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropylphenethylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-methylbenzyl)amide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-[2-(4-methoxyphenoxy)ethyl]amide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropylphenethylamide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-o-tolylehtyl)amide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-p-tolylethyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid(2-chlorobenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahyrdopyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,4-dimethoxybenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-6-fluorobenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-fluoro-2-methylbenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-difluorobenzyl)amide;4-{4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methylbenzyl)amide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(benzo[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethoxybenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-difluorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,4-dimethoxybenzyl)amide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(benzol[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl(2,3-dimethylbenzyl)amide;4-{4-[2-(2,6-dichloro-4-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethoxybenzyl)amide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-(4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,3-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(4-chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dichlorobenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-trifluoromethoxybenzyl)amide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(5-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (3-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethoxybenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(2,6-difluoro-3-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide;4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-difluorobenzyl)amide;4-{4-[2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chloro-3-trifluoromethylbenzyl)cyclopropylamide;4-{4-[2-(2,3-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[2-(2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-benzol[1,3]dioxol-5-yloxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxy-benzyl)amide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide;4-{4-[2-(4-chloro-2-methoxyphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[2-(2,3,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)ethylamide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2-fluoro-5-methoxybenzyl)amide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(3,5-dimethoxybenzyl)amide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[2-(4-chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid cyclopropyl-(2,3-dimethylbenzyl)amide4-{4-[2-(4-chloro-2-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide;4-{4-[2-(2-bromo-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-bromobenzyl)cyclopropylamide;4-{4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid cyclopropyl-(3-methoxybenzyl)amide;4-{4-[2-(2-chloro-4-trifluoromethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (6-chlorobenzo[1,3]dioxol-5-ylmethyl)-cyclopropylamide;4-{4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,4,5-trichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2-chloro-5-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2-chloro-3,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-(4-[2-(2-chloro-6-methylphenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,3-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,6-dichloro-4-fluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-(4-[2-(3-chloro-2,6-difluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,4,6-trifluorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide;4-{4-[2-(2,5-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide; and4-{4-[2-(2,6-dichlorophenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylicacid (2-chlorobenzyl)cyclopropylamide.
 7. A a compound of any one ofclaims 1-6 and a pharmaceutically acceptable carrier with or without anadjuvant.
 8. A method for the treatment or prophylaxis of a diseaseassociated with dysregulation of the rennin-angiotensin system (RAS),comprising administrating a compound according to any one of claims 1 to6 to a subject in need thereof.
 9. (canceled)
 10. (canceled)
 11. Themethod of claim 8, wherein said disease is selected from the groupconsisting of hypertension, congestive heart failure, pulmonaryhypertension, cardiac insufficiency, renal insufficiency, renal ormyocardial ischemia, atherosclerosis, renal failure, erectiledysfunction, glomerulonephritis, renal colic, glaucoma, diabeticcomplications, complications after vascular or cardiac surgery,restenosis, and complications of treatment with immunosuppressive agentsafter organ transplantation.
 12. The pharmaceutical composition of claim7, further comprising an additional pharmacologically active compoundselected from the group consisting of ACE inhibitors, angiotensin IIreceptor antagonists, endothelin receptor antagonists, vasodilators,calcium antagonists, potassium activators, diuretics, sympatholitics,beta-adrenergic antagonists and alpha-adrenergic antagonists.
 13. Amethod for treating or prevemtomg a disease associated withdysregulation of the RAS, comprising administering the pharmaceuticalcomposition of claim 7 to a subject in need thereof.
 14. A method fortreating or preventing a disease associated with dysregulation of theRAS, comprising administering the pharmaceutical composition of claim 12to a subject in need thereof.